The presence of endotoxins in the blood is called endotoxemia. It can lead to septic shock, if the immune response is severely pronounced. Moreover, endotoxemia of intestinal origin, especially, at the host-pathogen interface, is considered to be an important factor in the development of alcoholic hepatitis, which is likely to develop on the basis of the small bowel bacterial overgrowth syndrome and an increased intestinal permeability. It is also the source of neonatal necrotizing enterocolitis (NEC).
Lipopolysaccharides (LPS), including Lipid A may cause uncontrolled activation of mammalian immune systems with production of inflammatory mediators that may lead to septic shock. This inflammatory reaction is mediated by Toll-like receptor 4 (TLR4) which is responsible for immune system cell activation. Damage to the endothelial layer of blood vessels caused by these inflammatory mediators can lead to capillary leak syndrome, dilation of blood vessels and a decrease in cardiac function and can lead to septic shock. Pronounced complement activation can also be observed later in the course as the bacteria multiply in the blood. High bacterial proliferation triggering destructive endothelial damage can also lead to disseminated intravascular coagulation (DIC) with loss of function of certain internal organs such as the kidneys, adrenal glands and lungs due to compromised blood supply. The skin can show the effects of vascular damage often coupled with depletion of coagulation factors in the form of petechiae, purpura and ecchymoses. The limbs can also be affected, sometimes with devastating consequences such as the development of gangrene, requiring subsequent amputation. Loss of function of the adrenal glands can cause adrenal insufficiency and additional hemorrhage into the adrenals causes Waterhouse-Friderichsen syndrome, both of which can be life-threatening. It has also been reported that gonococcal LOS can cause damage to human fallopian tubes.
More specifically, NEC reflects the sudden inflammation and death of the infant's intestines, yet its causes remain obscure, and current therapy—which often includes surgery to remove the diseased intestine—still is associated with death in nearly half of patients. In seeking to identify the causes of NEC, the Hackam laboratory has identified that the premature infant intestine contains a TLR4 “switch”, which is “turned on” in premature babies by bacteria, leading to NEC. Prior studies have shown that the administration of breast milk is protective, although this is unfortunately only available for a minority of patients. Using computer assisted drug design, Hackam and colleagues recently identified a novel molecule, whose analogues are found in breast milk, and which can safely “shut off” the TLR4 switch in mice and piglets, after oral administration. The current disclosure examines the role of a new set of analogs for the prevention or treatment of NEC using a well validated mouse model.